The transcription factors TFE3 and TFEB cooperate to regulate autophagy induction and lysosome biogenesis in response to starvation. Here we demonstrate that DNA damage activates TFE3 and TFEB in a p53 and mTORC1 dependent manner. RNA-Seq analysis of TFEB/TFE3 double-knockout cells exposed to etoposide reveals a profound dysregulation of the DNA damage response, including upstream regulators and downstream p53 targets. TFE3 and TFEB contribute to sustain p53-dependent response by stabilizing p53 protein levels. In TFEB/TFE3 DKOs, p53 half-life is significantly decreased due to elevated Mdm2 levels. Transcriptional profiles of genes involved in lysosome membrane permeabilization and cell death pathways are dysregulated in TFEB/TFE3-depleted cells. Consequently, prolonged DNA damage results in impaired LMP and apoptosis induction. Finally, expression of multiple genes implicated in cell cycle control is altered in TFEB/TFE3 DKOs, revealing a previously unrecognized role of TFEB and TFE3 in the regulation of cell cycle checkpoints in response to stress.
- Eutteum Jeong
- Owen A Brady
- Jose A Martina
- Mehdi Pirooznia
- Iker Tunc
- Rosa Puertollano
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
- Hong Zhang, Institute of Biophysics, Chinese Academy of Sciences, China
- Received: August 6, 2018
- Accepted: December 3, 2018
- Accepted Manuscript published: December 6, 2018 (version 1)
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